Design and Synthesis ofN-(3,3-Diphenylpropenyl)alkanamides as a Novel Class of High-Affinity MT₂-Selective Melatonin Receptor Ligands

Abstract

A novel series of melatonin receptor ligands was discovered by opening the cyclic scaffolds of known classes of high affinity melatonin receptor antagonists, while retaining the pharmacophore elements postulated by previously described 3D-QSAR and receptor models. Compounds belonging to the classes of 2,3- and [3,3-diphenylprop(en)yl]alkanamides and of o- or [(m-benzyl)phenyl]ethyl-alkanamides were synthesized and tested on MT(1) and MT(2) receptors. The class of 3,3-diphenyl-propenyl-alkanamides was the most interesting one, with compounds having MT(2) receptor affinity similar to that of MLT, remarkable MT(2) selectivity, and partial agonist or antagonist behavior. In particular, the (E)-m-methoxy cyclobutanecarboxamido derivative 18f and the di-(m-methoxy) acetamido one, 18g, have sub-nM affinity for the MT(2) subtype, with more than 100-fold selectivity over MT(1), 18f being an antagonist and 18g a partial agonist on GTPgammaS test. Docking of 18g into a previously developed MT(2) receptor model showed a binding scheme consistent with that of other antagonists. The MT(2) expected binding affinities of the new compounds were calculated by a previously developed 3D-QSAR CoMFA model, giving satisfactory predictions.

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

“…A constrained side chain and a phenyl ring, fused with a five-membered ring mimicking the methoxy group, are present in the pyrrolidine derivative 20, a non-selective agonist with binding affinity similar to MLT (in its (R) configuration) and moderate stereoselectivity [130]. An open-chain analog approach, starting from tetralin and tricyclic scaffolds [131] and a subsequent replacement of a carbon with a nitrogen atom led to the class of anilinoethylamides [132], that include the non-selective agonist 21 and the MT 2 selective partial agonist UCM765 (Ki = 4.17 nM and 0.067 nM at MT 1 and MT 2 receptor, respectively).…”

Synthesis and pharmacological evaluation of 1,2,3,4-tetrahydropyrazino[1,2-a]indole and 2-[(phenylmethylamino)methyl]-1H-indole analogues as novel melatoninergic ligands

“…MeI; 2. KCN, CH 3 CN, dicylohexyl- [18]-crown [6]). For the synthesis of the cyanomethyl derivatives 18d-f, we applied another reaction sequence using our key intermediate 15 which was prepared via the aminomethylated 5-methoxyindole-2-carboxylic acid methyl ester 14 as previously reported.…”

“…The reaction mixture was stirred at room temperature for 15 h. The volatiles were removed in vacuo to afford 9a methoiodide. This crude ammonium salt was suspended in absolute acetonitrile (420 mL), dicyclohexyl-[18]-crown- [6] (2.70 g, 7.25 mmol) and potassium cyanide (5.29 g, 8.12 mmol) were added. The resulting reaction mixture was heated at reflux for 2.5 h. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3 Â 100 mL).…”

“…This crude ammonium salt was suspended in absolute acetonitrile (170 mL). Dicyclohexyl- [18]-crown- [6] (2.03 g, 5.45 mmol) and potassium cyanide (3.98 g, 61.1 mmol) were added and the resulting reaction mixture was heated at reflux for 3 h. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2 Â 50 mL). The organic layer was washed with water (2 Â 85 mL), dried (Na 2 SO 4 ) and evaporated in vacuo.…”

“…A common structural feature in most of the of MT 2 -selective antagonists is the presence of a lipophilic substituent located out-of-the plane of their core nucleus in a position corresponding to positions 1 and 2 in melatonin. 5 The most recently published series include N-(3,3-diphenylpropenyl)alkanamides, 6 N-substituted (anilinoethyl)amides, 7 3-phenylnaphthalenic derivatives, 8 and 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues, 9 However, there are only limited studies exploring the steric and electronic properties of the hydrophobic binding pocket accommodating this lipophilic group. [8][9][10][11][12][13] In the course of our studies on novel ligands for melatonin receptors, we have recently synthesized rigid pentacyclic compounds 2a-c (Fig.…”